The goal of this project is to study the influence of activity and pharmacotherapy on long-term histologic and functional outcome after experimental stroke in rats in order to develop a rational rehabilitation strategy and to optimize neuroprotective therapy. Substantial recovery occurs after stroke and this is modifiable by physical activity and drug administration during the first weeks after ictus. Forced overuse or disuse of the affected forelimb will increase infarct size, reduce new neuronal connections in cortex, and prevent recovery of forelimb motor activity. Impairment of normal calcium homeostasis and growth factor response inflammation, and DNA fragmentation in and around the ischemic region may conspire to produce delayed neuronal death and impaired function in response to overuse or disuse of the contralateral forelimb. Varying the pattern of motor intervention (rehabilitation) and various pharmacotherapies may enhance or retard these cellular processes and hence recovery depending upon when they are started or how long they are continued during the recovery period. Using a well-characterized model of focal ischemic damage that is aggravated by reperfusion ("reperfusion injury" model), we will test the effect of forced overuse or disuse by casting the forelimb contralateral or ipsilateral to the infarct during the first two weeks after ischemic insult. We will measure the effect of overuse or disuse on long-term recovery by quantitating forelimb placement and infarct volume. These results will be correlated with expression of growth factor (bFGF), inflammation (NFkB), apoptosis (TUNEL), and quantitation of neuronal loss (stereology) in histologic samples from the ischemic region. We will test our ability to modify these events and improve recovery by altering the casting paradigm thereby simulating different rehabilitation strategies, and by altering the time of onset and the duration of neuroprotective pharmacotherapy.